Provera

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Provera

WARNINGS

Cardiovascular disorders

An increased risk of stroke, deep vein thrombosis (DVT), pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

Coronary heart disease

In the estrogen plus progestin substudy of WHI, no statistically significant
increase of CHD events (defined as non-fatal myocardial infarction [MI], silent
MI or CHD death was reported in women receiving CE/MPA compared to women receiving
placebo (39 versus 33 per 10,000 women-years). An increase in relative risk
was demonstrated in year one, and a trend toward decreasing relative risk was
reported in years 2 through 5. (See Clinical Studies)

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE 0.625 mg/ MPA 2.5mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Venous thromboembolism (VTE)

In the estrogen plus progestin substudy of WHI, a statistically significant
two-fold greater rate of VTE, (DVT and pulmonary embolism [PE]), was reported
in women receiving daily CE/MPA compared to women receiving placebo (35 versus
17 per 10,000 women- years). Statistically significant increases in risk for
both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000
women-years) were also demonstrated. The increase in VTE risk was observed during
the first year and persisted. (See Clinical Studies)

Malignant neoplasms

Breast cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. Observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline in about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, doses, or routes of administration.

In the estrogen plus progestin substudy of WHI, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nominal confidence interval [nCI], 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Endometrial cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Ovarian cancer

The estrogen plus progestin substudy of WHI reported that daily CE/MPA increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent nCI, 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA was 4.2 versus 2.7 cases per 10,000 women-years.

After an average follow-up of 4 years, 40 women in the CE/MPA group and 21
women in the placebo group were diagnosed with probable dementia. The relative
risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI,
1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo
was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings
apply to younger postmenopausal women. (See BOXED WARNINGSand PRECAUTIONS, Geriatric Use.)

Visual Abnormalities

Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be permanently discontinued.

PRECAUTIONS

General

Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL) and impairment of glucose tolerance.

Undiagnosed abnormal vaginal bleeding

Elevated blood pressure

Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy.

Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

Impaired liver function and past history of cholestatic jaundice

Estrogens plus progestins may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.

Fluid Retention

Progestins may cause some degree of fluid retention. Patients who have conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen plus progestin are prescribed.

Hypocalcemia

Estrogen plus progestin therapy should be used with caution in individuals with severe hypocalcemia.

Exacerbation of other conditions

Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Patient Information

Physicians are advised to discuss the Patient Information
leaflet with patients for whom they prescribe PROVERA (medroxyprogesterone acetate tablets) .

There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to PROVERA (medroxyprogesterone acetate tablets) . Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of PROVERA (medroxyprogesterone acetate tablets) has not been established.

Inform the patient of the importance of reporting exposure to PROVERA (medroxyprogesterone acetate tablets) in early pregnancy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term intramuscular administration of PROVERA (medroxyprogesterone acetate tablets) has been shown to produce
mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect
associated with the oral administration of PROVERA (medroxyprogesterone acetate tablets) to rats and mice. Medroxyprogesterone
acetate was not mutagenic in a battery of in vitro or in vivo
genetic toxicity assays.

Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

Pregnancy

Pregnancy Category X: PROVERA should not be used during pregnancy. (SeeCONTRAINDICATIONS.)

There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to PROVERA (medroxyprogesterone acetate tablets) during the first trimester of pregnancy. However, a clear association between these conditions with use of PROVERA (medroxyprogesterone acetate tablets) has not been established.

Nursing Mothers

PROVERA (medroxyprogesterone acetate tablets) should not be used during lactation. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins.

Pediatric Use

PROVERA (medroxyprogesterone acetate tablets) is not intended for pediatric use and no clinical data has been collected in children.

Geriatric Use

Of the total number of subjects in the estrogen plus progestin substudy of the Women's Health Initiative (WHI), 44 percent (n = 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were 75 years and older. In women 75 and older compared to women less than 75 years of age, there was a higher relative risk of non-fatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75 years of age, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.

In the estrogen plus progestin Women's Health Iniative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women, aged 65 to 70 years, was randomized to receive daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.

Eighty-two percent of the cases of probable dementia occurred in women that were older than 70 in the CE/MPA group. The most common classification of probable dementia in the estrogen plus progestin and placebo groups was Alzheimer's disease.

When data from the estrogen alone and estrogen plus progestin WHIMS substudies
were pooled as planned in the WHIMS protocol, the reported overall relative
risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both substudies
were conducted in women aged 65 to 79 years, it is unknown whether these findings
apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

Last reviewed on RxList: 4/9/2008
This monograph has been modified to include the generic and brand name in many instances.